The present invention relates to a novel and improved method for the preparation of derivatives of uracil or, in particular, to a method for the preparation of N.sub.1 -(2-tetrahydrofuryl)uracil substituted or unsubstituted at the 5-position.
N.sub.1 -(2-Tetrahydrofuryl)-5-substituted uracil derivatives, for example, N.sub.1 -(2-tetrahydrofuryl)-5-fluorouracil, is a well known compound having therapeutic activity as an anti-tumor agent or an anti-leukaemia agent.
In the prior art, several methods are proposed for the synthetic preparation of N.sub.1 -(tetrahydrofuryl)uracil derivatives including (1) the reaction of 2,4-bis(trimethylsilyl)uracil, substituted or unsubstituted at the 5-position, with 2-chloro-, 2-acyloxy- or 2-alkoxytetrahydrofuran (see, for example, British Patent Specification No. 1,168,391, U.S. Pat. No. 3,912,734, Belgian Pat. No. 807,556 and Japanese Patent Publications Sho. No. 49-10510, Sho. No. 52-5517 and Sho. No. 52-5519), (2) the direct reaction of uracil, substituted or unsubstituted at the 5-position, with 2-chloro-, 2-acyloxy- or 2-alkoxytetrahydrofuran (see, for example, Japanese Patent Publication Sho. No. 52-5518 and Japanese Patent Disclosures Sho. No. 51-8282 and Sho. No. 51-52182), (3) the reaction of 2,4-bis(trialkylstannyl)uracil, substituted or unsubstituted at the 5-position, with 2-chloro-, 2-acyloxy- or 2-alkoxytetrahydrofuran (see, for example, German OLS No. 2,648,239 and Japanese Patent Disclosure Sho. No. 52-83473) and (4) the reaction of 2,4-bis(trimethylsilyl)uracil, substituted or unsubstituted at the 5-position, with 2,3-dihydrofuran (see, for example, Japanese Patent Disclosures Sho. No. 52-31079 and Sho. No. 52-59173, U.S. Pat. No. 4,039,546 and Belgian Pat. No. 830,215).
These prior art methods have, however, their own respective drawbacks. For example, the methods (1) and (4) with 2,4-bis (trimethylsilyl)-5-substituted uracil compounds as the starting material are quite disadvantageous industrially because the preparation of the starting material requires an extremely high temperature of 140.degree. to 170.degree. C. taking very long reaction time in the reaction of the silylation of 5-substituted uracil with a silylating agent, e.g. hexamethyldisilazane. The methods (1), (2) and (3) with 2-chloro-, 2-acyloxy- or 2-alkoxytetrahydrofuran as the alkylating agent at the N.sub.1 -position of the uracil compound are also disadvantaged by the step of the preparation of the 2-substituted tetrahydrofurans starting with 2,3-dihydrofuran as well as by the thermal instability of these 2-substituted tetrahydrofurans, especially 2-chlorotetrahydrofuran, even at room temperature.
In addition, the above described prior art methods, which take disadvantageously long reaction time generally, also suffer from the disadvantages due to the more or less inevitable formation of by-products such as 1,3-bis(2-tetrahydrofuryl)uracil derivatives along with the formation of the objective N.sub.1 -(2-tetrahydrofuryl)uracil derivatives necessitating additional process for the isolation and purification of the objective product resulting in undesirable lowering in the quality and yield of the product.
Recently an alternative method has been proposed in which an uracil compound substituted at the 5-position is directly reacted with 2,3-dihydrofuran in the presence of an accelerator for the reaction such as amine salts, combinations of an organic base and a metal halide or amphoteric compounds (see, for example, Japanese Patent Disclosure Sho. No. 52-89680 and German OLS Nos. 2,653,398 and 2,657,709). This method is also not free from the above described problems in the prior art methods though with somewhat improved yield of the product. In particular, the reaction of this method must be performed at an elevated temperature of 80.degree. to 200.degree. C. by use of an autoclave.